2-201768859-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020919.4(ALS2):c.20+7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,610,464 control chromosomes in the GnomAD database, including 23,992 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2488 hom., cov: 32)

Exomes 𝑓: 0.16 ( 21504 hom. )

Consequence

ALS2
NM_020919.4 splice_region, intron

Scores

Splicing: ADA: 0.00004604

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.406

Publications

15 publications found

Variant links:

Genes affected

ALS2 (HGNC:443): (alsin Rho guanine nucleotide exchange factor ALS2) The protein encoded by this gene contains an ATS1/RCC1-like domain, a RhoGEF domain, and a vacuolar protein sorting 9 (VPS9) domain, all of which are guanine-nucleotide exchange factors that activate members of the Ras superfamily of GTPases. The protein functions as a guanine nucleotide exchange factor for the small GTPase RAB5. The protein localizes with RAB5 on early endosomal compartments, and functions as a modulator for endosomal dynamics. Mutations in this gene result in several forms of juvenile lateral sclerosis and infantile-onset ascending spastic paralysis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

ALS2 Gene-Disease associations (from GenCC):

ALS2-related motor neuron disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
amyotrophic lateral sclerosis type 2, juvenile
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
infantile-onset ascending hereditary spastic paralysis
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
juvenile primary lateral sclerosis
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
juvenile amyotrophic lateral sclerosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ALS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 2-201768859-A-G is Benign according to our data. Variant chr2-201768859-A-G is described in ClinVar as Benign. ClinVar VariationId is 261367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.389 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020919.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ALS2	NM_020919.4	MANE Select	c.20+7T>C	splice_region intron	N/A	NP_065970.2
ALS2	NM_001410975.1		c.20+7T>C	splice_region intron	N/A	NP_001397904.1	A0A7P0T8F3
ALS2	NM_001135745.2		c.20+7T>C	splice_region intron	N/A	NP_001129217.1	Q96Q42-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ALS2	ENST00000264276.11	TSL:1 MANE Select	c.20+7T>C	splice_region intron	N/A	ENSP00000264276.6	Q96Q42-1
ALS2	ENST00000467448.5	TSL:1	c.20+7T>C	splice_region intron	N/A	ENSP00000429223.1	Q96Q42-2
ALS2	ENST00000482789.6	TSL:1	n.362+7T>C	splice_region intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.169

AC:

25708

AN:

151946

Hom.:

2488

Cov.:

show subpopulations

Gnomad AFR

AF:

0.186

Gnomad AMI

AF:

0.0724

Gnomad AMR

AF:

0.121

Gnomad ASJ

AF:

0.172

Gnomad EAS

AF:

0.403

Gnomad SAS

AF:

0.338

Gnomad FIN

AF:

0.222

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.133

Gnomad OTH

AF:

0.159

GnomAD2 exomes

AF:

0.194

AC:

48279

AN:

249128

AF XY:

0.199

show subpopulations

Gnomad AFR exome

AF:

0.192

Gnomad AMR exome

AF:

0.132

Gnomad ASJ exome

AF:

0.174

Gnomad EAS exome

AF:

0.411

Gnomad FIN exome

AF:

0.212

Gnomad NFE exome

AF:

0.141

Gnomad OTH exome

AF:

0.178

GnomAD4 exome

AF:

0.156

AC:

227951

AN:

1458402

Hom.:

21504

Cov.:

AF XY:

0.161

AC XY:

116933

AN XY:

725704

show subpopulations

African (AFR)

AF:

0.194

AC:

6492

AN:

33398

American (AMR)

AF:

0.136

AC:

6079

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.174

AC:

4537

AN:

26088

East Asian (EAS)

AF:

0.407

AC:

16136

AN:

39632

South Asian (SAS)

AF:

0.319

AC:

27497

AN:

86088

European-Finnish (FIN)

AF:

0.206

AC:

10997

AN:

53312

Middle Eastern (MID)

AF:

0.165

AC:

950

AN:

5758

European-Non Finnish (NFE)

AF:

0.130

AC:

144659

AN:

1109180

Other (OTH)

AF:

0.176

AC:

10604

AN:

60262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

8151

16302

24453

32604

40755

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5496

10992

16488

21984

27480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.169

AC:

25725

AN:

152062

Hom.:

2488

Cov.:

AF XY:

0.175

AC XY:

13022

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.186

AC:

7717

AN:

41494

American (AMR)

AF:

0.122

AC:

1860

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.172

AC:

598

AN:

3468

East Asian (EAS)

AF:

0.403

AC:

2082

AN:

5164

South Asian (SAS)

AF:

0.338

AC:

1630

AN:

4818

European-Finnish (FIN)

AF:

0.222

AC:

2346

AN:

10550

Middle Eastern (MID)

AF:

0.150

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.133

AC:

9046

AN:

67964

Other (OTH)

AF:

0.159

AC:

336

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1033

2067

3100

4134

5167

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

302

604

906

1208

1510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.145

Hom.:

3336

Bravo

AF:

0.163

Asia WGS

AF:

0.372

AC:

1288

AN:

3474

EpiCase

AF:

0.129

EpiControl

AF:

0.137

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Amyotrophic lateral sclerosis type 2, juvenile (2)

Infantile-onset ascending hereditary spastic paralysis (2)

not provided (2)

ALS2-related disorder (1)

Juvenile primary lateral sclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

4.5

(source)

DANN

Benign

0.61

PhyloP100

-0.41

PromoterAI

0.022

Neutral

(source)

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000046

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over